Late Complications of COVID-19; a Systematic Review of Current Evidence

Introduction: COVID-19 is a new rapidly spreading epidemic The symptoms of this disease could be diverse as the virus can affect any organ in the body of an infected person This study aimed to investigate the available evidence for long-term complications of COVID-19 Methods: This study was a systematic review of current evidence conducted in November 2020 to investigate probable late and long-term complications of COVID-19 We performed a systematic search, using the keywords, in online databases including PubMed, Scopus, Science Direct, Up to Date, and Web of Science, to find papers published from December 2019 to October 2020 Peer-reviewed original papers published in English, which met the eligibility criteria were included in the final report Addressing non-human studies, unavailability of the full-text document, and duplicated results in databases, were characteristics that led to exclusion of the papers from review Results: The full-texts of 65 articles have been reviewed We identified 10 potential late complications of COVID-19 A review of studies showed that lung injuries (n=31), venous/arterial thrombosis (n=28), heart injuries (n=26), cardiac/brain stroke (n=23), and neurological injuries (n=20) are the most frequent late complications of COVID-19 Conclusion: Since we are still at the early stages of the COVID-19 epidemic, it is too soon to predict what long-term complications are likely to appear in the survivors of the disease in years after recovery Furthermore, the complexity of COVID-19 behaviors and targets in the human body creates uncertainty in anticipating long-term complications


Introduction
Coronavirus disease 2019 (COVID-19) is an extremely contagious infectious disease caused by SARS-CoV-2 (1). COVID-19 infection was first reported in Wuhan, China, and spread quickly and turned into an unprecedented global pandemic (2)(3)(4)(5). The novel coronavirus affects not only the respiratory SA. SeyedAlinaghi et al. 2 and collection of heme in body tissues (10). SARS-CoV-2 usually affects the respiratory system (11), nervous system involvement has also been reported in some recent studies among patients with . Coronaviruses can attack the neural tissue including microglia, astrocytes, and macrophages, and cause nerve injury through direct nerve infection (13). The nervous system injuries could manifest as headache, dizziness, seizure, impaired consciousness, acute cerebrovascular disease, and ataxia. The virus could also affect the peripheral nervous system (PNS) and cause olfactory dysfunction, dysgeusia, vision impairment, and neuropathic pain (12, 13). COVID-19 could also cause cardiac injuries such as cardiomyopathy and conduction system malfunction. Studies suggest the direct involvement of cardiac muscles in some patients (4,14,15). Generally, infectious myocarditis is the most common cardiac complication of COVID-19 infection. SARS-CoV-2 uses the angiotensinconverting enzyme 2 (ACE2) receptors to infect host cells, through which it can cause pneumonia and myocardial injuries. High expression of ACE2 receptors in the lungs and heart could increase the risk of myocardial injuries in COVID-19 patients (14). ACE2 is also expressed in the intravascular endothelium, intestinal epithelium, and the kidneys; therefore, these organs could be a target for SARS-CoV-2 infection. Tachyarrhythmia is also a common cardiovascular complication in COVID-19 patients. Electrocardiography and echocardiography could be used in diagnosing and predicting the prognosis in COVID-19 patients (16). Some COVID-19 patients could suffer from earache that may be a sign of sub-acute thyroiditis. Studies have shown that a few weeks after upper respiratory tract involvement, subacute thyroiditis may occur and it might be a late complication in patients with COVID-19 infection. Therefore, thyroid functions should be checked after discharge in patients with 18). In addition, there is an abnormal rise in various biochemical parameters such as erythrocyte sedimentation rate (ESR), albumin levels, serum ferritin levels, lactate dehydrogenase (LDH) levels, and C-reactive protein (CRP) levels in the infected patients; on the other hand, the hemoglobin levels and lymphocyte count could reduce in these patients. These complications could lead to cytokine storm, causing multiple organ dysfunction (19,20). The coronavirus pandemic showed that COVID-19 could affect many organs besides the lungs, like heart and brain, which increases the risk of long-term health problems. There are several ways that the infection can affect someone's health. Much is still unknown about how COVID-19 will affect people over time. While most patients infected with COVID-19 recover quickly, the potential long-lasting problems caused by COVID-19 make it necessary to look for and study its late complications. This review aims to present a systematic review of late complications of COVID-19 and identify how prevalent these symptoms are and who is most likely to be affected by them.

Study design and setting
This study was a systematic review of current evidence conducted in October 2020 and subsequently updated on November 4, 2020. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was employed.

Data sources
We performed a systematic search using the keywords in the online databases including PubMed, Scopus, Science Direct, Up to Date, and Web of Science. All the related papers and reports published in English from December 2019 through October 2020 were retrieved and then updated in November 2020. Our search strategy in each of the above-mentioned databases included several combinations of keywords in the following orders: A. "Coronavirus" OR "COVID-19"OR"SARS-CoV-2" OR "Novel Coronavirus" OR "2019-nCoV" [Title/Abstract] B. "Clinical characteristics" OR "clinical feature" OR "clinical manifestation" [Title/Abstract] C. "Consequences" OR "Chronic complications" OR" Late complications" OR "Long-term effects" [Title/Abstract] D.

Study selection
The most relevant studies based on titles and abstracts were retrieved by three independent investigators. The full contents of the retrieved papers were reviewed, and the most relevant papers were selected based on the eligibility criteria. The relevant data were extracted and organized in tables. The peer-reviewed original papers published in English that met the eligibility criteria were included in the final report. The exclusion criteria were as follows: -Papers addressing non-human studies including in vitro investigations or publications concentrating on animal experiments, or discussing COVID-19 in general, without reference to the keywords of this study. -Unavailability of the full-text document. -Duplicated results in databases.

Data extraction
We used the data extraction sheet (Table 2) to summarize the information of the authors, type of article (e.g., case series), country of origin, study population, and clinical symptoms (late complications in this study). Two independent investigators gathered this information and further organized them in the Tables. All the selected articles were cross-checked by other authors to ensure no duplications or overlap exists in the content.

Quality assessment
For bias risk assessment, two independent reviewers rated the quality of included studies by applying the National Institute of Health (NIH) Quality Assessment Tools for Case Series Studies. For this purpose, we have designed a table and evaluated the studies according to NIH questionnaire (Table  1). A third independent investigator was consulted to resolve probable difference of opinions in any case. The full text of select articles was fully read and the key findings were extracted. The final report including the key findings is summarized in Table 2.

Results
We retrieved 1325 documents using a systematic search strategy. After an initial review of retrieved articles, 542 duplicates were removed, and the titles and abstracts of the remaining 783 articles were reviewed. Applying the selection criteria, 718 articles were excluded, and only 65 articles met the inclusion criteria and were included in the final review ( Figure 1). We identified 10 potential late complications of COVID-19 including neurological injuries, lung, liver, kidney, and heart injuries, thromboembolism, cardiac/brain stroke, encephalopathy, and psychological distress. Furthermore, some studies have pointed out other complications such as hypoproteinemia, septic shock, and multiple organ dysfunction syndromes ( Table 1). Review of studies showed that lung injuries (n=31), venous/arterial thrombosis (n=28), heart injuries (n=26), cardiac/brain stroke (n=23), and neurological injuries (n=20) were the most frequent late complications of COVID-19.

Discussion
One of the most important unknown features of COVID-19 is the duration of symptoms. In the early stages of the disease, the experts believed that the recovery time for mild cases of COVID-19 is 1-2 weeks (21). However, later in many patients, the symptoms lasted for 8 to 10 weeks or even longer, and in some cases, the initial symptoms were replaced by long-term complications such as lung or cardiac injuries (22). Since COVID-19 is a novel virus, there are limited studies about its late complications; it is just a few months since the recovery of the first patients in China. However, the available evidence suggests that the coronavirus can cause long-term complications in an infected person as it may cause major injuries to the heart, kidneys, brain, and even blood vessels (6, 10, 23, 24). The available evidence indicates the recurrence of symptoms in some patients who presented with severe initial symptoms (2,25,26). The key question is "what causes the recurrence of symptoms?". It may be caused by the re-currence or persistence of the primary COVID-19 infection or super infection with another virus or even bacteria due to the compromised immune system (27). In addition, the systemic and multiorgan involvement in advanced phases of COVID-19 pneumonia can cause renal failure, liver dysfunction, thrombocytopenia, and coagulation disorders (28). Therefore, the survivors may present a variety of long-term complications in different organs, including a post-recovery syndrome that doctors call "post-COVID lung disease" (29). By looking at the organs affected during an infection, one can imagine what organs are likely to be affected by longterm complications of COVID-19 infection (30). The most common long-term complication of COVID-19 is lung disease (8, 29, 31). Most of the COVID-19 patients could be recovered completely except for some minor complications such as cough and shortness of breath. However, a certain proportion of patients have excessive lung damage, and some of them develop pulmonary fibrosis (32). Autopsy studies demonstrated the predominance of microvascular thrombosis in the lungs, coincident with markers of inflammation, which is a hallmark of prolonged infection and sepsis (33). Severe lung involvement in COVID-19 patients could increase the likelihood of progression to chronic lung disease and lead to long-term complications (8, 33). COVID-19 patients may experience both venous and arterial thrombosis due to severe inflammation and hypoxia, long immobilization, and diffuse intravascular coagulation (27, 28). Klok et al. reported the incidence rate of thrombotic complications to be 31% among ICU patients with severe COVID-19 infection (27). The results of another study reported the high number of arterial and, in particular, venous thrombo-embolic late complications (34). Poggiali et al. described two patients with COVID-19 pneumonia who developed venous thromboembolism and reported hypoxia and sepsis as the potential risk factors for vein thromboembolism (VTE)(35). Recent studies reported an increased risk of heart failure in COVID-19 patients (26, 28, 30). Moreover, episodes of clinical myocarditis have been observed (15). Heart injuries related to COVID-19 may occur over the course of the disease(36). Late involvement of cardiac muscle has been documented in a study by Puntmannet al. In this study, the researchers investigated the cardiac complications in 100 recovered patients; 78% of patients had cardiac involvement in cardiac magnetic resonance imaging (MRI), 76% had detectable highsensitivity troponin, and 60% had abnormal native T1 and T2, which indicates the presence of active myocardial (37). Compared to the control group with similar preexisting conditions, left ventricle ejection fraction was lower and the ventricular size was higher in COVID-19 patients. In addition, 32% of patients had late gadolinium enhancement and 22% of them had pericardial involvement (36, 37). COVID-19 can cause damage to the central nervous system, with po-tentially long-term consequences (38-41). Late neurological complications of COVID-19, whether caused by the virus or by the triggered inflammation, include decreased awareness and absorption, disturbed memory, and dysfunction of the peripheral nervous system (42). In one study from China, more than a third of hospitalized patients with confirmed COVID-19 had neurological symptoms, including dizziness, headaches, impaired consciousness, vision, taste/smell impairment, and nerve pain. These symptoms were more common in patients with severe disease, where the incidence increased to almost 47 percent (43). Another study in France found neurologic features in 58 of 64 critically ill COVID-19 patients (25).

Conclusion
Since we are still at the early stages of the COVID-19 epidemic, it is too soon to predict what long-term complications are likely to appear in the survivors of the disease in years after recovery. Furthermore, the complexity of COVID-19 behaviors and variety of its targets in the human body create uncertainty in anticipating long-term complications. However, several ongoing studies are set up to examine the physical, psychological, and socio-economic consequences of the COVID-19.

Acknowledgment
The present study was conducted in collaboration with Khalkhal University of Medical Sciences, Iranian Institute for Reduction of High-Risk Behaviors, Tehran University of Medical Sciences, and Department of Global Health and Socioepidemiology, Kyoto University. (1) The conception and design of the study: Esmaeil Mehraeen, SeyedAhmad SeyedAlinaghi

Ethics approval and consent to participate
The present study was extracted from the research project with code IR.KHALUMS.REC.1399.001 entitled "Investiga-tion of effective drugs for people affected by Coronavirus disease 2019 (COVID-19) in selected hospitals in Ardabil" conducted at Khalkhal University of Medical Sciences in 2020.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

Consent to publication
Not applicable

Availability of data and material
The authors stated that all information provided in this article are available.    Archives of Academic Emergency Medicine. 2021; 9(1): e14  (69) Yes Yes CD NA NA Yes CD Yes Yes Fair Fair NA: not applicable; NIH: National Institutes of Health; NR: not reported; CD: cannot determine *The NIH Quality Assessment Tool for Case Series Studies contains nine questions: 1 = Was the study question or objective clearly stated?, 2 = Was the study population clearly and fully described, including a case definition?, 3 = Were the cases consecutive?, 4 = Were the subjects comparable?, 5 = Was the intervention clearly described?, 6 = Were the outcome measures clearly defined, 7 = Was the length of follow-up adequate?, 8 = Were the statistical methods well-described?, 9 = Were the results well-described? Yes Yes NA CD NA Yes CD Yes Yes Fair Fair NA: not applicable; NIH: National Institutes of Health; NR: not reported; CD: cannot determine *The NIH Quality Assessment Tool for Case Series Studies contains nine questions: 1 = Was the study question or objective clearly stated?, 2 = Was the study population clearly and fully described, including a case definition?, 3 = Were the cases consecutive?, 4 = Were the subjects comparable?, 5 = Was the intervention clearly described?, 6 = Were the outcome measures clearly defined, 7 = Was the length of follow-up adequate?, 8 = Were the statistical methods well-described?, 9 = Were the results well-described?